2-nitroimidazole derivatives substituted in the 1-position with a 2-oxo-propyl or semicarbazone group

ABSTRACT

ANTIMICROBIAL 2-NITROIMIDAZOLE DERIVATIVES SUBSTITUTED IN THE 1-POSITION WITH A 2-OXO-PROYL OR SEMICARBAZONE GROUP, A 2-PROPANOL GROUP, A 2,3-EPOXYPROPYL GROUP OR DERIVATIVES THEREOF.

United States Patent U.S. C]. 260-309 Claims ABSTRACT OF THE DISCLOSURE Antimicrobial 2-nitroimidazole derivatives substituted in the 1-position with a 2-oxo-propyl or semicarbazone group, a 2-propanol group, a 2,3-epoxyprop-yl group, or derivatives thereof.

CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisional application of Ser. No. 840,077 filed Apr. 23, 1969 now U.S. Pat. 3,549,653, which in turn is a divisional application of our application Ser. No. 556,585 filed June 10, 1966, now U.S. Pat. No. 3,468,902, Sept. 23, 1969, which is a continuation-inpart of our application Ser. No. 447,087 filed April 9, 1965, now abandoned.

DETAILED DESCRIPTION OF THE INVENTION ahe present invention relates to l-substituted nitroimidazoles and, more particularly, relates to l-substituted- 2-nitroimidazoles of the formula I Z I wherein R and R are each independently selected from the group consisting of hydrogen and lower alkyl; Z represents one of the following groups:

R is hydrogen, halogen, hydroxyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, halo-lower alkoxy, polyhalo-lower alkoxy, halo-lower alkynyloxy, phenoxy or phenoxy in which one or more of the hydrogens has been replaced by halogen, lower alkyl or lower alkoxy; and acyl represents lower alkanoyl, benzoyl or benzoyl in which one or more of the hydrogens has been replaced by halogen, lower alkyl or lower alkoxy and pharmaceutically acceptable salts thereof. I

In one of its specific aspects the invention relates to compounds of the formula ice wherein R and R have the same meaning as above and pharmaceutically acceptable salts thereof.

In another specific aspect of the invention relates to compounds of the formula III wherein R R and R have the same meaning as above and pharmaceutically acceptable salts thereof.

In another specific aspect the invention relates to compounds of the formula wherein R R R and acyl have the same meaning as above wherein R R and R have the same meaning as above and pharmaceutically acceptable salts thereof.

In yet another specific aspect the invention relates to compounds of the formula wherein R R and K, have the same meaning as above and pharmaceutically acceptable salts thereof.

As used throughout this application the terms halo, halogen and the like denote all four halogens, i.e., bromine, chlorine, iodine and fluorine. The term lower alk denotes saturated aliphatic hydrocarbons containing 1 to 7 carbon atoms both straight and branched chain, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tbutyl and the like. The term lower alkoxy denotes lower alkyl ether groups wherein the lower alkyl portion is as defined above. The term lower alkenytloxy denotes an unsaturated alpihatic hydrocarbon ether group preferably containing only one double bond such as vinyloxy, allyloxy, 1,2-butenyloxy, 2,3-butenyloxy and the like. The term lower alkynyloxy denotes unsaturated aliphatic hydrocarbon ether groupscontaining at least one triple bond such as ethinyloxy, propynyloxy, butynyloxy and the like. The term acyl denotes the acid residue of an organic acid preferably a lower alkanoic acid, e.g., acetic acid, propionic acid, butenoic acid and like, or benzoic acid of a benzoic acid derivative such as halo-benzoic acid, toluic acid, p-methoxybenzoic acid and the like.

Compounds of Formula III are prepared by reacting Z-nitroimidazole with 1,2-propylene oxide or an appropriately substituted oxirane derivative, i.e., 3-R -1,2-propylene oxide wherein R has the same meaning as above. As exemplary oxirane derivatives suitable for use in this reaction, there can be named the following:

1,2-epoxy-3-halo-propane 1,2-epoxy-3-hydroxy-propane 1,2-epoxy-3-lower alkoxy-propanes, e.g., 1,2-epoxy-3-methoxy-propane, 1,2-epoxy-3-ethoxy-propane, 1,2- epoxy-3-propoxy-propane, etc.

1,2-epoxy-3-lower alkenyloxy-propanes, e.g., 1,2-epoxy- 3-vinyloxy-propane, 1,2-epoxy-3-allyloxy propane, 1,2-epoxy-3-butenyl-propane, etc.

1,2-epoxy-3-(halogeno-lower alkoxy)propanes, e.g., 1,2-epoxy-3-chloromethoxy-propane, 1,2-epoxy-3- (fi-chloroethoxy) propane, 1,2-epoxy-3-trifiuoromethoxy-propane, 1,2epoxy-3-(fi,B,fl-trifluoroethoxy)propane, 1,2-epoxy-3-(u-chloro-[3- chloroethoxy)propane, etc.

l,2-epoxy-3-(halogeno-lower alkynyloxy)propanes, e.g.,

1,2-epoxy-3- 3-iodo-2-propynyloxy propane, etc.

1,2-epoXy-3-phenoxy-propane 1,2-epoxy-3- (halo-phenoxy propane 1,2-epoxy-3-( lower alkylphenoxy)propane 1,2-epoxy-3-(lower alkoxyphenoxy) propane and the like.

The reaction with epihalohydrins or with other appropriately substituted oxirane derivatives to form compounds of Formula III can be suitably carried out at an elevated temperature preferably a temperature in the range of about 50 C. to about 150 C. and preferably in the presence of an acid neutralizing agent such as an alkali metal hydroxide, e.g., sodium hydroxide, potassium hydroxide, etc., an alkali metal carbonate, e.g., sodium or potassium carbonate, an amine such an ammonia, or the like, or, if desired, in the absence of an acid neutralizing agent. The oxirane may serve as a solvent, or an alcohol such as ethanol may also be employed as solvent. Water may also be used as solvent.

Certain of the compounds of Formula III can also be prepared by alternative processes. Thus, for example, the diols of Formula III, i.e., compounds of Formula III wherein R is hydroxyl, can be prepared from the corresponding epoxides of Formula II by treatment with a suitable acid such as sulfuric acid, hydrofluoric acid and the like. The epoxides of Formula II are in turn prepared by treating the compounds of Formula HI where R is halogen with base, e.g., sodium hydroxide and the like. Compounds of Formula III wherein R is bromo or chloro can also be prepared from the epoxide of Formula II by treating with the approriate hydrohalic acid.

The compounds of Formula IV are prepared by forming an ester of a compound of Formula III by treating with any of the conventional acylating agents such as lower alkanoic acid, benzoic acid, subsituted benzoic acid, benzene sulfonic acid, p-toluene sulfonic acid and esterforming derivatives thereof such as the corresponding anhydrides or acid halides, e.g., acid chlorides. Compounds of Formula V, namely the 1-(2-nitro-l-imidazolyl)-3-R propan-2-ones are prepared by reacting a compound of Formula III in a ketone solvent such as acetone in the presence of a chromate solution. The reaction is preferably carried out at about room temperature though higher or lower temperatures, e.g., temperatures in the range of about to 100 C., could also be used. Compounds of Formu a V wherein R is hydrogen are also prepared by reacting the appropriate. 2-nitroimidazole derivativewith a halo acetone, e.g., chloro acetone, in the presence of an alkali metal lower alkoxide, e.g., sodium methoxide, potassium ethoxide and the like, preferably in the presence of an inertorganic solvent, e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and the like.

Compounds of Formula-VI are prepared from compounds of Formula V by reacting with semicarbazide or a suitable salt thereof in the presence of an alkali metal acetate, e.g., sodium acetate trihydrate. The reaction is suitably carried out in an inert organic solvent such as a lower alkanol, e.g., methanol, ethanol and the like, and is preferably carried out at an elevated temperature between about room temperature and the boiling point of the reaction mixture.

The compounds of Formula I and their acid addition salts with pharmaceutically acceptable acids are useful as antimicrobial agents. They are particularly useful against bacterial, fungi, pathogenic yeasts and protozoa, for example, against Trichomonas vaginalis, Trichomonas foetus, Histomonas malegradis, 'Endamaeba histolytica, T rypanosomes, e.g., T. cruzi, T. rhodesieuse, T. cougoleuse, and the like, and can therefore, be used as germicides, anti-protozoal agents, e.g., 'trichomonacides, histomonacides, trypanacides, and agents for the treatment of pathogenic yeast infections.

Compounds of Formula III are particularly well suited for the treatment of protozoal infections, e.g., trichomoniasis and histomoniasis and those compounds of Formula III wherein R is hydrogen, hydroxy, halo, i.e., chloro, bromo, fluoro or iodo, alkoxy, especially methoxy, and haloalkoxy, constitute a preferred group.

For use in the treatment of infectious diseases such as trichomoniasis, trypanosomiasis, histomoniasis, etc., the compounds of this invention can be administered orally, parenterally or topically. They can be formulated into conventional pharmaceutical dosage forms in admixture with organic or inorganic inert carrier materials which are suitable for enteral, parenteral or topical application such as, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gum arabic, polyalkylene glycols, Vaseline, etc. or other conventional excipients. They can be prepared in the form of tablets, drages, suppositories, capsules, ointments, creams, etc., or in liquid form such as solutions, suspensions, emulsions and the like. They can contain other additives such as preserving, stabilizing, Wetting or emulsifying agents, salts for varying the osmotic pressure, buffers and the like or they can be formulated with other therapeutically useful materials. Typical oral dosages of the novel compounds of this invention and their salts range from about 10 to about mg./ kg. animal body weight though higher or lower dosages adjusted to species and individual requirements may also be used.

,Acid addition salts of the novel compounds of this invention, i.e., the compounds of Formula I, are prepared by reacting with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., or with organic acids such as oxalic acid, acetic acid, lactic acid, tartaric acid and the like. Non-pharmaceutically acceptable acid addition salts can be converted into pharmaceutically ac ceptable acid addition salts by neutralization followed by reaction with a suitable pharmaceutically acceptable acid.

The novel products of this invention and their use will be more fully understood from the examples which follow. These examples are intended to illustrate the invention and are not to be construed as limitative thereof.

EXAMPLE 1 Preparation of 1-(2-nitro-1-imidazolyl)-3- chloro-2-propanol A mixture of 52.3 g. (462 mmoles) of powdered sublimed 2-nitroimidazole, 315 ml. of epichlorohydrin and 5.25 g. of anhydrous potassium carbonate was stirred and heated. When boiling commenced the heating mantle was shut off, but left in place and the reaction mixture was boiled briskly for minutes. The hot mixture was filtered and the insoluble material was washed with boiling ethanol. From the refrigerated filtrate crude product was obtained. This was recrystallized from 1100 ml. of boiling ethanol to give 1-(2-nitro-l-imidazolyl)-3-chloro-2-propanol as yellow crystals, melting point 156158.

A1232? 315 m a: 7800 EXAMPLE 2 Preparation of 1- (2,3-epoxypropyl)-2-nitroimidazole 250 ml. of 10 percent aqueous sodium hydroxide solution was stirred at room temperature and 38.13 g. (185 mmoles) of finely powdered 1-(2-nitro-1-imidazolyl)-3- chloro-2-propanol was added and beaten into suspension. In one or two minutes, the solid dissolved and in two or three minutes a new, crystalline solid began to form. The slurry was stirred at room temperature for 5 to minutes and was then cooled in a Dry Ice bath until it began to freeze. The mixture was filtered and the solid was washed with 40 ml. of ice cold distilled water, slurried in 50 ml. of ice cold distilled water, refiltered, washed with two times 40 ml. of ice cold distilled water and dried. The pale yellow crystalline solid melted at 5355. It was dissolved in 250 ml. of distilled water at 60, the solution treated with charcoal, and the filtrate refrigerated to give nearly colorless crystals of l-(2,3-epoxypropyl)-2-ni troimidazole, melting point 53.5-55

AEEQF 310 m e=7800 EXAMPLE 3 Preparation of 1-(2-nitro-1-imidazolyl)- 3-bromo-2-propanol AEtOH max.

EXAMPLE 4 Preparation of 1-(Z-nitro-l-imidazolyl)-2-propanol A mixture of 5 .00 g. (44.2 mmoles) of powdered sublimed 2-nitroimidazole, 0.60 g. (4.3 mmoles) of anhydrous potassium carbonate and about 75-100 ml. of propylene oxide was heated at 90-113 for 2% hours in a rocking autoclave under 700 pounds of nitrogen pressure. The 2-nitroirnidazole had dissolved and the product remained in solution at room temperature. The K CO was filtered and the propylene oxide removed in vacuo to give an amber oil which gradually partially solidified on cooling. This was slurried in ml. of benzene at room temperature, filtered and washed with 10 ml. of benzene. The crude solid was recrystallized from 20 ml. of boiling absolute ethanol to give pale yellow chunky crystals of l-(2-nitro-l-imidazolyl)-2-propanol, melting point ll9.5-l21.

EtOH max.

drous potassium carbonate, and 49' ml. of 1,2-epoxy-3- methoxypropane was stirred and boiled (109-114") for ethanol. It was recrystallized from ml. of absolute.

ethanol to give off-white crystals of l-(2-nitro-l-imidazolyl)-3-methoxy-2-propanol, melting point -11l.

EXAMPLE 6 Preparation of 1-(2-nitro-1-imidazolyl)-3-methoxy-2- propanol A mixture of 30.0 g. of ground and sieved sublimed 2- nitroimidazole, 3.00 g. of anhydrous potassium carbonate, 48.5 ml. (47.3 g.) of 1,2-epoxy-3-methoxypropane and 225 ml. of absolute ethanol was refluxed with stirring. After the solution had become clear except for K 00 and a bit of haze (about 30-45 min.), the refluxing was continued for an additional 30 minutes. The reaction mixture was filtered hot, Washing with a little hot absolute ethanol. The filtrate was refrigerated overnight. The chunky amber crystals were filtered, washed with 25 ml. of ethanol and dried. The crude product was recrystallized from 340 ml. of boiling ethanol (Norit A) and the filtrate refrigerated overnight to give l-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol as light yellow crystals, M.P. 110ll1.

A2132? 314 mu, 6: 7400 EXAMPLE 7 Preparation of 1-(2-nitro-1-imidazolyl)-2-propanone A slurry of 10.44 g. (92.4 mmoles) of sublimed 2- nitroimidazole in 100 ml. of N,N-dimethylformamide was dissolved to a red solution by the addition of 20.8 ml. of 4.44 N sodium methoxide in methanol solution. Enough Z-nitroimidazole was added to change the color of the solution to yellow. With stirring the solution was heated to 153 to remove the methanol and cooled to 60. With stirring 10 ml. (11.5 g.) of chloroacetone was added. The temperature rose spontaneously to 73 over a period of 7 minutes and a precipitate of NaCl formed. The mixture was then heated to 114 over a period of 15 minutes with stirring, and was then cooled. The mixture was evaporated to an oil in vacuo (0.2 mm. Hg, bath 30-40). The oil was diluted with 70 ml. of absolute ethanol and the solid which precipitated was filtered, washed with 20 ml. of ethanol and dried. This was boiled with 225 ml. of benzene and filtered from NaCl. From the filtrate on cooling there formed nearly colorless lathshaped crystals of 1-(2-nitro-1-imidazolyl)-2-propanone, melting point 75-76.

A212? 318 m e=7500 EXAMPLE 8 Preparation of 3-(2-nitro-1-imidazolyl)-1,2-propanediol A solution of 8.00 g. (47.2 mmoles) of 1-(2,3-epoxypropyl)-2-nitroimidazole in 48 ml. of 6 N sulfuric acid was heated at 60-65 for 15 minutes with stirring. The solution was cooled and neutralized to pH 7 at a temperature below 0 by the slow addition of 18 ml. of concentrated aqueous ammonia with stirring. The solution was extracted with two 500 ml. portions of ethyl acetate and the solvent removed in vacuo to give a solid which was ground in a mortar with 30- ml. of distilled water at room temperature and filtered from an insoluble impurity. The water was evaporated and the obtained solid was recrystallized from 50 ml. of absolute ethanol (charcoal) to give crystalline 3-(2-nitro-l-imidazolyl) 1,2-propanediol, M.P. 1l0112.

EtOH rnax.

7 EXAMPLE 9 Preparation of 3-(Z-nitro-l-imidazolyl)-1,2-propanediol A mixture of 40.2 g. (355 mmoles) of powdered and sieved sublimed 2-nitroimidazole, 300 ml. of absolute ethanol, 4.00 g. of anh. K CO and 47 ml. (52.5 g., den. 1.12, 710 mmoles) of glycidol was refluxed with stirring until the UV spectrum in 0.1 N NaOH indicated no unreacted Z-nitroimidazole (40 min). (At this stage the reaction mixture was a clear amber solution.) The EtOH was removed in vacuo to give a dark amber oil which was dissolved in 100 ml. of cold distilled water. The pH of the solution was adjusted to 7 with 8.5 ml. of 2 N HCl and the solution was then extracted with times 700 ml. of ethyl acetate. The ethyl acetate extracts were allowed to evaporate in shallow dishes to give a sticky solid. The combined extract was ground in a mortar with 150 ml. of ethanol, filtered, washed with 3 times 10 ml. of ethanol and dried. Recrystallized from 325 ml. of boiling absolute ethanol (-5 g. Norit A), there was obtained 3- (2-nitro-1-imidazolyl)-1,2-propanediol as pale yellow crystals, M.P. 110-111", having an infrared spectrum identical to that of the material prepared from 1-(2,3- epoxypropyl) 2-nitroimidazole.

EXAMPLE 10 Preparation of 1-(Z-nitro-1-imidazolyl)-3-iodo-2- propanol A232? 317 m e=6900 EXAMPLE 11 Preparation of 1-(2-nitro-1-imidazolyl)3-fluoro-2- propanol Powdered sublimed 2-nitroimidazole (2.00 g.) plus 0.20 g. of anhydrous K CO plus 5.0 ml. of epifluorohydrin was stirred and refluxed until the solid dissolved except for the K CO (52 minutes). The solution was diluted with 10 ml. of boiling absolute ethanol, filtered and cooled to .give crude material which was recrystallized from ethanol to give nearly colorless crystals of 1-(2- nitro-l-imidazolyl)3-fluoro-2 propanol, melting point 139.5140.

AECOH EXAMPLE 12 Preparation of 1-(2-nitro-1-imidazolyl) 3-chloro-2- propanolacetate Powdered 1'(2-nitro-1-imidazolyl)3-chloro-2-propanol (1.08 g.) plus 10 ml. of acetic anhydride was refluxed for 15 minutes. The acetic anhydride was removed in vacuo (oil pump) and 5 ml. of absolute ethanol was added and removed in vacuo. Then 5-8 ml. of absolute ethanol was added and the solid which formed was collected (melting point 151-1535", presumably starting material). The ethanol was evaporated and the resulting gum was dissolved in 5 ml. of CI-ICl filtered, and 4 ml. of hexane added and the mixture cooled. A tar formed. The supernatant liquid was decanted and 2 ml. of hexane was added. An oil formed. The mixture was heated, filtered, and the light yellow filtrate cooled, yielding an oil. The solvent was decanted and the oil dried (1.3 mm., 80) for 1 hour. 1(2-nitro-l-imidazolyl)3-chloro-2-propanolacetate was obtained thereby.

8 EXAMPLE 13 max.

369 In e=11,900

EXAMPLE 14 Preparation of 1-(2-nitro-l-imidazolyl)-3-fluoro2- propanol A mixture of 22.5 g. (199 mmoles) of powdered and sieved sublimed Z-nitroimidazole', 2.25 g. anhydrous p0- tassium carbonate, ml. of absolute ethanol and 29.1 g. (382 mmoles) of epifluorohydrin was stirred and refluxed. After 47 minutes the solution was completely clear except for chunks of K CO After53minutes reflux the hot solution was filtered. The filtrate was allowed to stand at room temperature for 1 hr. and was then refrigerated for 2% hours. The crystals which had formed were filtered and washed with 25 ml. of absolute ethanol. They were recrystallized from 230 ml. of ethanol (3.2 g. charcoal) to give pale yellow crystals, M.P. 137.5-139.5. A sample was recrystallized again from 10 parts of absolute ethanol to give chunky crystals of 1-(2-nitro-l-imidazolyl)-3-fluoro-2-propanol, M.P. 139.5-".

AEtOH max.

Preparation of l- (Z-nitro-l-imidazolyl) 3-chloro-2- propanone Eight grams (39 mmoles) of 1-(2-nitro-1-imidazolyl)- 3-chloro-2-propanol was dissolved in 200 ml. of boiling reagent acetone and the solution was cooled to 29. With stirring 10.0 ml. of CrO solution (26.7 mmoles equivalent to 40 mmoles of the propanol) was added. (The CrO solution used in this preparation contained 266.7 g./l. of CrO M.W. 100.0 plus 230 ml. concentrated H SO /1. Thus 1 ml. contained 2.67 mmoles CrO which is equivalent to 4 mmoles of CHOH.) The temperature rose to 36.5 over 15 minutes and then fell. At 20 minutes, 30 minutes and 50 minutes (total reaction times) 3 /3 ml. portions of CrO solution were added.

The reaction mixture was stirred for a total of 1.5 hrs. and 200 ml. of distilled water was added. The solution was cooled to 20, neutralized to pH 7.0 by the slow addition of 9 ml. of concentrated ammonia solution; The solid which formed was filtered and the filtrate extracted with 700 ml. of ethyl acetate. The ethyl acetate extract was dried and evaporated to an oil atwater aspirator vacuum. The oil solidified upon trituration with ether and the solid was collected. It was dissolvedin 300 ml. of boiling reagent benzene and the decantate was allowed to stand quietly for about an hour. Hazy material was removed by filtration and from the filtrate crystals of 1- (2-nitro-l-imidazolyl)3-chloro-2-propanone, M.P. 91.5- 93 were obtained (standing over weekend).

A523? 313 m e=7400 UV study in 0.1 NaOH indicates the material is destroyed rapidly by base at room temperature.

9 EXAMPLE 16 Preparation of l-(2-nitro-1-imidazolyl)-3-(2-chloroethoxy)-2-propanol A mixture of 50.0 g. (442 mmoles) of powdered and sieved sublimed 2-nitroimidazole, 5.00 g. of anhydrous potassium carbonate, 420 ml. of absolute ethanol and EXAMPLE 17 Preparation of 1-(2-nitro-1-imidazolyl)-3-chloro-2- propanol anisate Anisoyl chloride (3.0 g., 17.6 mmoles) was dissolved in 60 ml. of anhydrous pyridine (distilled from BaO) and the solution was cooled to 5. Then 3.0 g. (14.6 mmoles) of 1-(2-nitro-l-imidazolyl)-3-chloro-2-propanol was added (dissolved readily). The solution was allowed to stand in an ice bath for 2 hrs. and was then allowed to warm to room temperature (5.5 hrs.). The solution was evaporated to an oil in vacuo. This was shaken thoroughly with a mixture of 30 ml. of ethyl acetate plus 30 ml. of saturated aqueous sodium carbonate. The organic layer was separated and extracted in turn with 2x 30 ml. of saturated Na CO solution, 3X 30 ml. of l N HCl and 3X 30 ml. of distilled water. The EtOAc layer was dried over anhydrous MgSO and concentrated to an oil in vacuo. This was dissolved in -15 ml. of benzene. Crystals, M.P. 97.5101, formed upon standing over the weekend. These were crystallized twice more from absolute ethanol to give 1-(2-nitro-1-imidazolyl)-3-chloro- 2-propanol anisate as crystals, M.P. 106-1075".

258, 312 my, e=19,800; 7500 EXAMPLE 1-8 AEtOH max.

A mixture of 15.1 g. (133 mmoles) of powdered and sieved sublimed 2-nitroimidazole, 1.51 g. anhydrous potassium carbonate, 75 ml. of absolute ethanol and 30 ml. (28.8 g., 282 mmoles) of 1,2-epoxy-3-ethoxypropane was stirred and refluxed for 1.75 hr. The mixture was filtered and the filtrate evaporated to a light amber colored oil in vacuo (0.2 mm. bath 45). The oil was slurried in 25 ml. of ethanol at room temperature, filtered and the filtrate allowed to evaporate in a petri dish to give an oil which gradually crystallized. The oil was allowed to stand one week to permit reasonably complete crystallization. The crystals, wet with an amber oily material, were mixed thoroughly with about 6 ml. of room temperature absolute ethanol and filtered. This removed much of the amber oil. The solid was dried and dissolved in 110 m1. of boiling benzene, filtered and the filtrate cooled near the freezing point of benzene. The fiakelet crystals which formed were collected, washed with 10 ml. of benzene and dried, M.P. 52.5-54.5. This was dissolved in 18 ml. of hot ethanol and the solution cooled in the freezer overnight to give needles of 1-(2 nitro-l-imidazolyl)-3-ethoxy-2-propanol which were collected, washed with 2 ml. of cold (freezer) absolute ethanol and dried, M.P. 58.59.

A232? 317 m e=7200 10 EXAMPLE 19 Preparation of 1-(2-nitro-1-irnidazolyl)-3-phenoxy- 2-propanol A mixture of 5.07 g. (44 mmoles) of powdered and sieved sublimed 2-nitroimidazole, 0.51 g. of anhydrous potassium carbonate, 10.0 ml. (11.0 g., 73 mmoles) of 1,2-epoxy-3-phenoxypropane and 50 ml. of absolute ethanol was stirred and refluxed. After 1 hr. 20 minutes reflux the solution was clear except for K CO After 15 minutes more reflux the solution was filtered and the filtrate refrigerated. The solid which formed was collected, washed with 2X10 ml. of absolute ethanol (removes most of the color) and dried. This was recrystallized from ml. of boiling absolute ethanol (charcoal) to give 1-(2-nitro-l-imidazolyl)-3-phenoxy-2-propanol as crystals, M.P. 1425-1435".

max.

Preparation of 1-(2-nitro-1-imidazoyl)-3-(2,4-dichlorophenoxy)-2-propanol A mixture of 10.0 g. (88.4 mmoles) of ground and sieved sublimed Z-nitroimidazole, 100 ml. of absoulte ethanol, 1.00 g. anhydrous K 00 and 26.2 ml. (35.9 g., 164 mmoles, den. 1.37) of 1,2-epoxy-3-(2,4-dichlorophenoxy)propane was refluxed with stirring until the UV spectrum of the reaction mixture in 0.1 N NaOH showed a maximum at 328 mp. and no sign of a shoulder near 370 m The hot mixture was filtered, the insoluble solid washed with hot ethanol and dried. The filtrate was refrigerated to give additional product. The total product was recrystallized from 700 ml. of boiling absolute ethanol (charcoal) to give 1-(2-nitro-1-imidazolyl)-3- (2,4-dichlorophenoxy)-2-propanol as crystals, M.P. 162.

max.

EXAMPLE 21 Preparation of l-(2-nitro-1-imidazolyl) -3-methoxy- 2-propanone The temperature rose to 35 over a period of 10 minutes and then fell, Then at 20 minutes and 35 minutes (total reaction times) 5 ml. portions of CrO solution were added. The reaction mixture was stirred for a total of one hour, cooled in an ice bath and 300 ml. of distilled water was added. The solution was cooled to 18 and neutralized to pH 5 by the dropwise addition of 8 ml. of concentrated aqueous ammonia solution with stirring. The hazy solution was filtered and the filtrate extracted with 1200 ml. of ethyl acetate. The organic layer was dried over Drierite, filtered and the filtrate evaporated in vacuo to give an oil. Sixty ml. of ether was added and the oil soon solidified. The solid was ground in a mortar with the ether, filtered and recrystallized from 100 ml. of boiling benzene to give 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanone as crystals, M.P.. 65-66.

315 mp, e=7300 The compound was unstable in solution in 0.1 N NaOH, the UV absorption being rapidly lost,

11. EXAMPLE 22 Preparation of 1-(2-nitro-1-imidazoly1)-3 (2- chloroethoxy) -2-propanone To a stirred solution of 10.16 g. (40.7 mmoles) 'of 1-(2-nitro-1-imidazolyl)-3-(2 chloroethoxy)-2-propanol in 250 ml. of reagent grade acetone at 20 was added ml. of CrO solution. (This solution contained 266.7 CrO M.W. 100.0, plus 230 ml. of concentrated H 50; diluted to 1 l. with H O; thus, 1 ml. contained 2.67

m'rnoles of CrO which is equivalent to 4.0 mmoles of CHOH-.) The temperature rose to 32 over a period of 8 minutes. Then at 17 minutes and 46 minutes (total reaction times) 3 /3 ml. portions of CrO solution were added. The reaction mixture was stirred for a total of 1% hr., cooled in an ice bath and 250 ml. of distilled water was added. The solution was cooled to 9 and neutralized to pH 5 by the dropwise addition of 5 ml. of concentrated aqueous ammonia solution with stirring. The hazy solution was filtered and the filtrate extracted with 1 l. of ethyl acetate. The organic layer was dried over Drierite, filtered and the filtrate evaporated to an oil in vacuo. Fifty mil. of ether was added and the oil soon solidified. The solid was ground in a mortar with the ether, filtrated and recrystallized twice from 90 ml. of boiling benzene to give crystalline 1-(2-nitro- 1-imidazolyl)-3 (2-chloroethoxy) 2-propanone, M.P. 69.5-71".

A523? 315 m e=7300 EXAMPLE 23 Preparation of 1-(2-nitrol-imidazolyl)- 3- (Z-chlorophenoxy) -2-propanol A mixture of 10.0 g. (88.4 mmoles) of ground and sieved sublimed 2-nitroimidazole, 100 ml. of absolute ethanol, 26.6 ml. (32.6 g., 176.8 mmoles, den. 1.22) of 1,2-epoxy-3-(2-chlorophenoxy) propane and 1.00 g. of anhydrous K CO was refluxed with stirring until the solution became clear except for K CO (45 minutes) and then for an additional minutes. The hot reaction mixture was filtered and the filtrate was refrigerated overnight to give a light colored product. This was crystallized from 300 ml. of boiling ethanol (charcoal) to give 1-(2- nitro 1 imidazolyl)-3-(2-chlorophenoxy)-2-propanol as crystals, M.P. 130-132.

EXAMPLE 24 Preparation of 1-(2-nitro-l-imidazolyl)- 3-isopropoxy-2-propanol A mixture of 10.0 g. (88.4 mmoles) of ground and sieved sublimed 2-nitroimidazole, 1.0 g. of anhydrous K CO 100 ml. of absolute ethanol and 22.5 ml. (20.6 g., 176.8 mmoles, den. 0912) of 1,2-epoxy-3-isopropoxypropane was refluxed with stirring until mas 330 and there was no shoulder at 370 m z (about 2 hours). The hot solution was filtered and the filtrate allowed to evaporate in a shallow dish togive an oil which solidified upon trituration with ether. The solid was filtered, washed with ether and recrystallized from 32 ml. of boiling ethanol (charcoal) to give crystalline 1-(2-nitro-1- imidazolyl)-3-isopropoxy-2-propanol, M.P. 63-65 Am) 314 m e=6700 max.

EXAMPLE 25 Preparation of 1-(2-nitro-1-imidazolyl)- 3-propoxy-2-propanol pane was refluxed with stirring for 1.5 hrs. (UV curve shows 1 and only slight inflection-372 mg.) The hot solution Was filtered .and the filtrate placed in the freezer over, the weekend. The clear supernatant liquid was decanted from a little solid (M.P. 220-225 dec.) and the decantate was allowed to evaporate in a shallow dish. The resulting moist solid was mixed thoroughly with 6-7 ml. room temperature absolute ethanol, filtered, washed with 3 ml. absolute EtOH and dried. The crude product was a mixture which was fractionated by repeated crystallizations from benzene, ethanol and water to give a less soluble'material as fiakelets, M.P. 130.5-134.5"- and amore soluble crystalline material, M.P. 74.5-76. v

AELOH The material, M.P. 74.5-76f, was the desired 1- 2-nin-bl-imidazolyl)-3-propoxy-2-propanol.

EXAMPLE 26 Preparation of 1-(2-nitro-1-imidazo1yl)- 2-propanone semicarbazone 1-(2-nitro-1-imidazolyl)-2-prop'anone (9.05 g., 53.5 mmoles) was dissolved in ml. of warm ethanol and 90 ml. of distilled water was added. Then 9.05 g. of semicarbazide hydrochloride was added (stirred until dissolved) and then 13.6 g. of sodium acetate trihydrate was added (stirred until dissolved). The solution was heated. At 45 crystals began to form. The mixture was stirred near the boil for 15 minutes and was then refrigerated. The needles which formed were collected, washed with l:1vol.:vol. H O:EtOH and dried, M.P. 222-223 dec. A small sample was recrystallized from volumes of boiling ethanol to give 1-(2-nitro-1-imidazolyl)-2-propanone semicarbazone as fine crystals, M.P. 224-225" dec.

A1223? 310 my, e =4500 EXAMPLE 27 Preparation of I-(Z-nitro-I-imidazolyl) 3-methoxy-2-propanol anisate A solution of 9.00 g. (52.8 mmoles) of anisoyl chloride in ml. of reagent pyridine (distilled and dried over BaO) was cooled to 5 in an ice bath. Then 9.00 g. (44.7 mmoles) of 1-(2-nitro-l-imidazolyl)-3-methoxy-2- propanol was added and the solution was allowed to stand in the ice bath for 1.5 hrs. The solution was evaporated in vacuo to an oil plus solids. This Was dissolved in'a mixture of 100 ml. of ethyl acetate plus 50 of 1 N HCl. The layers were separated and the ethyl acetate layer Was extracted in turn with 2x 25 mli'of 1 N'HCl, 1X 25 ml. saturated Na CO solution and 3 x 25 ml.-- of water. The EtOAc layer was dried over anhydrous Na SO and concentrated in vacuo to an amber oil. This was tritu'rated with ether (30 ml.) and seeded. The crystals which formed were filtered, Washed thoroughly with ether and dried, M.P. 72-73.5. This was recrystallized from 50 ml. of methanol (1 g. Norit A) to give 1-(2-nitro-1-imidazolyl')- 3-methoxy-2-propanol anistate as crystals, M.P. 7375'.'

x3532, 258, 313 my, vt="19,300, 7200 EXAMPLE 28f I Preparation of 1-(2-rlitro-1-imidazo1yl) V 3-methoxy-2-propanone semicarbazone To a solution of 0.40 g. (2.01 mmoles) of 1-(2-nitro- 1-imidazolyl)-3-methoxy-2propanone'in 5 ml. of ethanol was added 5 ml. of water. Then 0.40 g. of semicarbazide hydrochloride was added (stirred until dissolved) followed by 0.60 g. of sodium acetate trihydrate (stirred until dissolved). The solution was heated near the boil for 15 minutes (no solid formed) and was placed in the freezer overnight. The solid which formed was filtered and washed with 3 ml. and then 2 ml. of 1:1 vol.:vol. EtOH:H O and dried, M.P. 181-1 83 dec. It was recrystallized from 35 ml. of boiling ethanol to give shiny fiakelets of 1-(2- nitro 1 imidazolyl)-3-methoxy-2-propanone semicarbazone, M.P. 186-187 dec.

A232? 314 mp, e=7000 EXAMPLE 29 Preparation of 1-(2-nitro-l-imidazolyl)-3-(2-chl0roethoxy) -2-propanone semicarbazone To a solution of 0.90 g. (3.6 mmoles) of 1-(2-nitro-1- imidazolyl)-3 (2-chloroethoxy)-2-propanone in 10 ml. of ethanol was added 10 ml. of water. Then 0.90 g. of semicarbazide hydrochloride was added (stirred until dissolved) followed by 1.35 g. of sodium acetate trihydrate (stirred until dissolved). The solution was heated near the boil for 20 minutes (no solid formed) and was refrigerated overnight to give an oil. The supernatant liquid was decanted away and the oil was washed by decantation with two times 1.5 ml. of 1:1 vol.:vol. EtOH:H O and soon thereafter the oil solidified. It was ground in 3 ml. of ethanol, filtered, washed with 1-2 ml. of ethanol and dried, M.P. 153%-154 /2 It was recrystallized from 20 ml. of boiling absolute ethanol to give 1-(2-nitro-1- imidazolyl) 3 (2 chloroethoxy) 2 propanone-semicarbazone as colorless fine needles, M.P. 156 /2-157".

AELOH m, 316 my, e=7000 EXAMPLE 30 Preparation of 1-(Z-nitro-l-imidazolyl)-3-allyloxy-2- propanol A mixture of 10.0 g. (88.4 mmoles) of ground and sieved sublimed 2-nitroimidazole, 1.00 g. of anhydrous K CO 100 m1. of absolute ethanol and 21.5 ml. (den. 0.975, 20.95 g., 184 mmoles) of 1,2-epoxy-3-allyloxypropane was stirred and refluxed for 1.5 hrs. during which time the solution became essentially clear except for K CO The solution was filtered and the filtrate allowed to evaporate in a shallow dish to give an oil which gradually set to a moist crystalline solid. This was ground in a mortar with a mixture of 15 ml. of ether plus 4 ml. benzene, filtered and washed with 5 ml. of 5 percent EtOH 95 percent benzene mixture and dried. It was recrystallized from 15 ml. benzene plus 0.75 ml. absolute ethanol (5 percent ethanol 95 percent benzene) and refrigerated to give crystals. (Washing the crystals with the 5 percent ethanol 95 percent benzene mixture at room temperature removed some amber oil from the crystals.) These were recrystallizedfrom ml. benzene+0.5 ml. absolute ethanol to give 1-(2-nitro-1-imidazolyl)-3-allyloxy-2-propanol as crystals, M.P. 57.558.5.

XELOH mm 318 mp, 6=550O EXAMPLE 31 Preparation of 1-(2-nitro-1-imidazolyl)-3-(2,3-dibromoprop oxy -2-propanol To a solution of 1.00 g. (4.40 mmoles) of 1-(2-nitrol-imidazolyl)-3-allyloxy-2-propanol in 10 ml. of CHCl was added a solution of 0.30 ml. (den. 2.93, 0.88 g., 5.5 mmoles) of bromine in 5.5 ml. CHCl at room temperature dropwise with stirring as long as the bromine bleached rapidly. About 4.5 ml. (4.5 mmoles bromine) was required. The mixture was allowed to stand for 30 minutes and the hazy solution was filtered and the filtrate was allowed to evaporate'in a shallow dish. The residual oil was tn'turated with ether and allowed to stand overnight. The resulting sticky solid was slurried in a mixture of 5 ml. of benzene plus 5 drops of ether and filtered, washed with benzene and dried, M.P. 60-72. This was dissolved in 5 ml. of hot benzene and the solution cooled and the yellow solid which formed was collected, M.P. below 50. The filtrate was refrigerated overnight to give EtOH rm.

317 mp, e=8200 EXAMPLE 32 Preparation of 1-(2-nitro-1-imidazolyl)-3-(2,2,2-trifluoroethoxy) 2-propanol A mixture of 10.0 g. of (88.5 mmoles) of ground and sieved sublimed 2-nitroimidazole plus 1.10 g. anhydrous K CO plus 100 ml. of absolute ethanol plus 23.0 ml. (den. 1.26, 29.1 g., 186 mmoles) of 1,2-epoxy-3-(2,2,2- trifluoroethoxy)propane was stirred magnetically and refluxed for 1 /3 hours during which time the solution became clear except for K CO and a bit of haze. The hot solution was filtered and the filtrate was allowed to evaporate to dryness in a shollow dish. The hard, moist crust of solid was ground in a mortar with 10 ml. of absolute ethanol, filtered and washed with 2x 5 ml. of room temperature absolute ethanol and dried, M.P. 93-98". This was recrystallized from 150 ml. of boiling absolute ethanol (5 g. charcoal) (cooling in freezer) to give 1-(2- nitro 1 imidazolyl) 3 (2,2,2 trifiuoroethoxy) 2- propanol as colorless crystals, M.P. 95-965.

A212 315 m e=7500 EXAMPLE 33 Preparation of 1-(2-nitro-1-imidazolyl)-3-methoxy- 2-propano1 A mixture of 1.00 g. (8.85 mmoles) of sublimed 2- nitro-imidazole, 2 ml. of 1,2-epoxy-3-methoxypropane, 0.1 g. of potassium carbonate and 10 ml. of distilled water was refluxed for 20 min. and cooled to give 1-(2- nitro 1 imidazolyl) 3 methoxy 2 propanol as crystals, M.P. 109110.5 and having an IR. spectrum identical to that of the compound prepared using ethanol as the solvent.

Identical results were obtained when the 0.1 g. of potassium carbonate used above was replaced by either 0.05 g. of sodium hydroxide or by 0.1 ml. of concentrated aqueous ammonia solution.

EXAMPLE 34 Preparation of 1-(2-nitro-l-imidazolyl)-3-methoxy-2- propanol acetate A solution of 9.57 g. (47.6 mmoles) of 1-(2-nitro-1- imidazolyl)-3-methoxy-2-propanol in 90 ml. of dry pyridine was cooled to 5 and 7 ml. of acetylchloride was added slowly with stirring maintaining the temperature between 5 and 10. The mixture was allowed to stand in an ice bath for 30 min. and was then let warm to room temperature. The solvent was removed in vacuo (0.3 mm., bath 35) and the residue was dissolved in a mixture of 200 ml. of ethyl acetate plus ml. of 0.1 N

HCl. The layers were separated and the ethyl acetate layer was then extracted in turn with 4 times 100 ml. of 0.1 N HCl, 2 times 50 ml. of aqueous sodium carbonate solution and 3 times 50 ml. of distilled water. It was then dried over anhydrous sodium sulfate, filtered and the ethyl acetate was removed in vacuo to give an oil which crystallized on cooling and scratching the walls of the vessel. This was recrystallized from 25 ml. of CCl (1 g. of Norit A) and then twice from 10 parts of ether to give 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol acetate as crystals, M.P. 62-64".

gility Na mp,

g: NaOH 71 e=12,000

EXAMPLE 36 Preparation of 1-(2-nitro-1-imidazolyl) -3- (3-iodo-2- propynyloxy) -2-propanol To a cooled solution of 15.0 g. (372 mmoles) of sodium hydroxide in 150 ml. of distilled water was added 50.8 g. (279 mmoles) of 3-iodopropargyl alcohol plus 28.0 ml. (358 mmoles) of epichlorohydrin and the mixture was stirred at room temperature for 18 hrs. The layers were separated and the lower organic layer was warmed in vacuo (0.3 mm., bath 60) to remove water and epichlorohydrin. The 1,2-epoxy-3-(3-iodo-2-propynyloxy)propane product so obtained was dried over Drierite and used without further purification.

A mixture of 7.01 g. (62.0 mmoles) of ground and sieved sublimed 2-nitroimidazole, 0.6 9 g. of anhydrous potassium carbonate, 48.6 g. of 1,2-epoxy-3-(3-iodo-2- propynyloxy)propane (prepared as described hereinabove) and 100 ml. of absolute ethanol was stirred and refi'uxed for one hour. The hot solution was filtered and the filtrate was allowed to evaporate to give an oil which was repeatedly dissolved in ethanol and the ethanol allowed to evaporate until the oil partially solidified. The

mixture was slurried with 40 ml. of ethanol and the solid was filtered, washed with ethanol and dried, M.P. 99.5- 103". This was recrystallized twice from 5 parts of ethanol to give 1-(2-nitro-1-imidazolyl)-3-(3-iodo-2-propynyloxy)-2-propanol as crystals, M.P. 103-104.

N 315 m e=7200 max.

EXAMPLE 37 Preparation of 1-(2-nitro-1-imidazolyl)-3- methoxy-Z-propanol EXAMPLE 38 This example illustrates typical pharmaceutical formulations incorporatingas active ingredient the novel compounds of this invention.

CAPSULE FORMULATION v 7 Mg. per capsule Compound of Formula I, II or HI 2 Lactose 143 Corn starch 37 Talc Total weight 210 Procedure (I) The compound of Formula III or III, lactose and corn starch were mixed in a suitable mixer.

(2) The mixture was further blended by passing through a Fitzpatrick comminuting machine with a No. 1A screen with knives forward.

(3) The blended powder was returned to the mixer, the talc added and blended thoroughly. The mixture was filled into No. 4' hard shell gelatin capsules'on a capsulating machine. I

TABLET FORMULATION Mg. per tablet Compound of Formula I, II, III Q 25.0 Lactose 93.5 Corn starch 70.5 Pregelatinized corn starch 8.0 Calcium stearate 3.0

Total weight 200.0

Procedure (1) The compound of Formula I, II, HI, lactose, corn starch and pregelatinized corn starch were mixed in a suitable size mixer.

(2) The mix was passed through a Fitzpatrick comminuting machine fitted with No. 1A screen and with knives forward. I

(3) The mix was then returned to the mixer and moistened with water to a thick paste. The moist mass was passed through a No. 12 screen and the moist granules were dried on paper lined trays at F.

(4) The dried granules were returned to the mixer, the

calcium stearate was added and mixed well.

(5) The granules were compressed at a tablet weight of 200 mg. using standard concave punches having a diameter of 7 PARENTERAL FORMULATION Per cc. Compound of Formula I, II, III mg 5.1 Propylene glycol cc 0.4 Benzyl alcohol (benzaldehyde free) cc 0.015 'Ethanol (anhydrous) cc 0.10 Sodium benzoate mg 48.8 Benzoic acid mg 1.2

Water for injection, q.s. 1.0 cc.

Procedure (for 10,000 cc.)

(1) The 51 gms. of the compound of Formula I, II or III were dissolved in cc. of benzyl alcohol; 4,000 cc. of propylene glycol and 1,000 cc. of ethanol were added.

(2) The 12 gms. of benzoic acid were dissolved in the above. The 488 gms. of sodium benzoate dissolved in 3,000 cc. of water for injection were added. The solution was brought up to final volume of 10,000 cc. with water for injection. 7

(3) The solution was filtered through an 02 Selas candle, filled into suitable size ampuls, gassed with N and sealed. It was then autoclaved at 10 p.s.i. for 30 minutes.

SUPPOSITORY FORMULATION Gm. per.1.3 gm.

. suppository Compound of Formula I, II or III 0.010 Refined synthetic cocoa butter-coconut derived 1.245 Carnauba wax 0.045

Procedure (3) The mixture was poured into suppository molds to yield suppositories having an individual weight of 1.3 gms.

(4) The suppositories were removed from molds and cooled. They were individually wrapped in wax paper for packaging.

TOPICAL CREAM Gm. per 100 gms. cream Compounds of Formula I, II or III 5.1 Stearic acid 15.0

Mineral oil light 1.5 Sorbitan monostearate 2.5 Methyl p-hydroxybenzoate 0.08 Propyl p-hydroxybenzoate 0.02 Sorbitol solution N.F 5.00 Polyoxyethylene sorbitan monostearate 1.69 Distilled water 72.5

Procedure 1) The stearic acid, mineral oil, sorbitan monostearate and methyl and propyl p-hydroxybenzoates were melted together at approximately 75 C. in a suitable size stainless steel, jacketed kettle with agitator.

(2) A suspension of the compound of Formula I, II or III in a solution of polyoxyethylene sorbitan monostearate, sorbitol NP. and distilled water was added to the melted mixture.

(3) The mixture was stirred at 75 C. until uniform and the temperature was gradually reduced with continuous stirring.

(4) When the temperature reached 48 C., the cream was transferred to storage containers.

(5) The cream was packaged in wax lined, tin tubes (opal glass jars may also be used).

We claim: 1. A compound of the formula wherein R and R are each independently selected from the group consisting of hydrogen and lower alkyl; Z represents one of the following groups:

i.e., a compound of the formula wherein R R and R are as above.

3. The compound according to claim 2 wherein R R and R are each hydrogen, i.e., the compound 1-(2-nitrol-imidazolyl) -2-propanone.

4. The compound according to claim 2 wherein R and R are each hydrogen and R is chloro, i.e., the compound 1-(2-nitro-l-imidazolyl)-3-chloro-2-propanone.

5. The compound according to claim 2 wherein R and R are each hydrogen and R is methoxy, i.e., the compound 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanone.

6. The compound according to claim 2 wherein R and R are each hydrogen and R is 2-chloroethoxy, i.e., the compound 1 (2-nitro-1-imidazolyl)-3-(2-chloroethoxy)- 2-propanone.

7. A compound according to claim 1 wherein Z represents the group i.e., a compound of the formula CH -C-CH -R N-NHCONH:

References Cited UNITED STATES PATENTS 3,268,558 8/1966 Karmas 260-309 3,472,864 10/1969 Henry et al 260309 OTHER REFERENCES Kochergin et al. Chem. Abst. vol. 51, column 1942 (1957). QD1.A51.

Lawson et al., Chem. Abst. vol. 50, columns 7104-5 (1956). QD1.A51.

Perekalin et al., Chem. Abst. vol. 46, column 8115 (1952). QD1.A51.

Ratusky et al., Chem. Abst. vol. 51, column 13,843 (1957). QD1.A51.

Ried et al., Chem. Abst. vol. 50, column 366-7 (1956). QD1.A51.

NATALIE TROUSOF, Primary Examiner US. Cl. X.R. 

